Theoretical and experimental transport models of high-flow microinfusion into brain tissue have indicated the feasibility of delivering macromolecules over cm distances in either grey or white matter. To address remaining issues of infusion control and monitoring, a study was undertaken in monkeys with 111-In-DTPA-transferrin to determine: (a) penetration distances and volumes achievable with long-term white matter infusions using implantable programmable pumps; (b) long-term clearance rates of the protein from the infused region; (c) the magnitude of the effect of microinfusion on blood perfusion rates to brain; and (d) whether SPECT could be used to assess these factors noninvasively during the course of infusion. Drug was infused at an average flow rate of 1.9microl/min for 87 hrs, and planar and SPECT images of both the infused protein and regional perfusion marker HMPAO were obtained on days 1,3,4,8, and 11 following beginning of infusion; autoradiography was obtained from another monkey sacrificed 9 hrs post-infusion. An intensity threshold of 39% that was applied to the D-V SPECT image yielded a width matched to the D-V white matter spread measured directly on autoradiograms. A-P, M-L, and D-V spreads at end of infusion were 2.7 cm, 2.2 cm, and 2.9 cm, respectively. Infusion volumes over 3 monkeys ranged from 4.9 ml to 6.7 ml. Post-infusion tissue clearance determined from absorption-corrected planar images was 0.118 plus minus 0.033 microl/min/ml, suggestive of clearance by extrachoroidal fluid production and flow. Local perfusion reduction was small (on the order of 3.4%).